The mechanism of bile duct destruction in Primary Biliary Cirrhosis

• Project/Area Number: 22590739
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyushu University
• Principal Investigator: SHIMODA Shinji 九州大学, 大学病院, 講師 (30279319)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 原発生胆汁性肝硬変 / 自然免疫 / モデルマウス / 原発性胆汁性肝硬変 / NK細胞 / 胆管破壊 / 肝臓浸潤単核球 / 胆管上皮細胞 / TLR3リガンド / TLR4リガンド / 単球 / IFN-a

Research Abstract

Primary biliary cirrhosis (PBC) is characterized by chronic nonsuppurative destructive cholangitis (CNSDC) associated with destruction of small bile ducts. We examined the role of Toll-like receptors (TLRs), their ligands, and natural killer (NK) cells in modulating cytotoxic activity against biliary epithelial cells (BECs). We demonstrate that Toll-like receptor 4 ligand (TLR4-L)-stimulated NK cells destroy autologous BECs in the presence of interferon alpha (IFN-α) synthesized by TLR 3 ligand (TLR3-L)-stimulated monocytes (Mo). Indeed, IFN-α production by hepatic Mo is significantly increased in patients with PBC compared to disease controls. These data are supported by the immunohistochemical observation of an increased presence of CD56-positive NK cells scattered around destroyed small bile ducts more frequently in liver tissues from PBC patients than controls. To clarify the role of innate immune effector cells, such as natural killer (NK) cells, was studied in the mouse model based on the hypothesis that early events during immunization play an important role in the breakdown of tolerance. Following in-vivo depletion of NK cells, there is a marked suppression of anti-mitochondrial autoantibodies and cytokine production from autoreactive T cells. However, there was no change in the clinical pathology of portal inflammation compared to controls. These data support the hypothesis that there are probably multiple steps in the natural history of PBC, including a role of NK cells in initiating the breakdown of tolerance.

Research Products

• [Journal Article] Vigorous cleaning and adequate ventilation are necessary to control an outbreak in a neonatal intensive care unit (2012)
  • Author(s): Shimono N, Hayashi J, Matsumoto H, Miyake N, Uchida Y, Shimoda S, Furusyo N, Akashi K
  • Journal Title: J Infect Chemother Volume: 18(3) Pages: 303-7
  • NAID: 10030787099
  • Peer Reviewed
• [Journal Article] The role of natural killer (NK) and NK T cells in the loss of tolerance in murine primary biliary cirrhosis. (2012)
  • Author(s): Shimoda Shinji
  • Journal Title: Clin Exp Immunol. Volume: Jun;168(3) Pages: 279-84
  • Peer Reviewed
• [Journal Article] Significance of immunoglobulin G4 (IgG4)-positive cells in extrahepatic cholangiocarcinoma: molecular mechanism of IgG4 reaction in cancer tissue. (2012)
  • Author(s): Harada Kenichi
  • Journal Title: Hepatology Volume: Jul;56(1) Pages: 157-64
  • Peer Reviewed
• [Journal Article] Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population. (2012)
  • Author(s): Nakamura Minoru
  • Journal Title: Am J Hum Genet. Volume: Oct 5;91(4) Pages: 721-8
  • Peer Reviewed
• [Journal Article] Fractalkine and other chemokines in primary biliary cirrhosis. (2012)
  • Author(s): Shimoda Shinji
  • Journal Title: Int J Hepatol. Volume: 102839 Pages: 1-5
  • Peer Reviewed
• [Journal Article] Epigenetic investigation of variably X chromosome inactivated genes in monozygotic female twins discordant for primary biliary cirrhosis (2011)
  • Author(s): Mitchell MM, Lleo A, Zammataro L, Mayo MJ, Invernizzi P, Bach N, Shimoda S, Gordon S, Podda M, Gershwin ME, Selmi C, LaSalle JM
  • Journal Title: Epigenetics Volume: 6(1) Pages: 95-102
  • Peer Reviewed
• [Journal Article] Significance of periductal Langerhans cells and biliary epithelial cell-derived macrophage inflammatory protein-3a in the pathogenesis of primary biliary cirrhosis (2011)
  • Author(s): Harada K, Shimoda S, Ikeda H, Chiba M, Hsu M, Sato Y, Kobayashi M, Ren XS, Ohta H, Kasashima S, Kawashima A, Nakanuma Y
  • Journal Title: Liver Int Volume: 31(2) Pages: 245-53
  • Peer Reviewed
• [Journal Article] Intracellular B7-H4 suppresses bile duct epithelial cell apoptosis in human primary biliary cirrhosis (2011)
  • Author(s): Chen Y, Guo G, Guo S, Shimoda S, Shroyer KR, Tang Y, Wu Y
  • Journal Title: Inflammation Volume: 34(6) Pages: 688-97
  • Peer Reviewed
• [Journal Article] Interaction between Toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis (2011)
  • Author(s): Shimoda S, Harada K, Niiro H, Shirabe K, Taketomi A, Maehara Y, Tsuneyama K, Nakanuma Y, Leung P, Ansari AA, Gershwin ME, Akashi K
  • Journal Title: Hepatology Volume: 53(4) Pages: 1270-81
  • Peer Reviewed
• [Journal Article] Modulation of CD4 T cell responses following splenectomy in hepatitis C virus-related liver cirrhosis (2011)
  • Author(s): Hashimoto N, Shimoda S, Kawanaka H, Tsuneyama K, Uehara H, Akahoshi T, Kinjo N, Taketomi A, Shirabe K, Akashi K, Lleo A, Ansari AA, Gershwin ME, Maehara Y
  • Journal Title: Clin Exp Immunol Volume: 165(2) Pages: 243-50
  • Peer Reviewed
• [Journal Article] Fine phenotypic and functional characterization of effector cluster of differentiation 8 positive T cells in human patients with primary biliary cirrhosis (2011)
  • Author(s): Tsuda M, Ambrosini YM, Zhang W, Yang GX, Ando Y, Rong G, Tsuneyama K, Sumida K, Shimoda S, Bowlus CL, Leung PS, He XS, Coppel RL, Ansari AA, Lian ZX, Gershwin ME
  • Journal Title: Hepatology Volume: 54(4) Pages: 1293-302
  • Peer Reviewed
• [Journal Article] Significance of periductal Langerhans cells and biliary epithelial cell-derived macrophage inflammatory protein-3α in the pathogenesis of primary biliary cirrhosis (2011)
  • Author(s): Harada K, Shimoda S, Ikeda H, Chiba M, Hsu M, Sato Y, Kobayashi M, Ren XS, Ohta H, Kasashima S, Kawashima A, Nakanuma Y
  • Journal Title: Liver Int Volume: Feb;31(2) Pages: 245-53
  • Peer Reviewed
• [Journal Article] Modulation of CD4^+ T cell responses following splenectomy in hepatitis C virus-related liver cirrhosis (2011)
  • Author(s): Hashimoto N, Shimoda S, Kawanaka H, Tsuneyama K, Uehara H, Akahoshi T, Kinjo N, Taketomi A, Shirabe K, Akashi K, Lleo A, Ansari AA, Gershwin ME, Maehara Y
  • Journal Title: Clin Exp Immunol Volume: Aug;165(2) Pages: 243-50
  • Peer Reviewed
• [Journal Article] Epigenetic investigation of variably X chromosome inactivated genes in monozygotic female twins discordant for primary biliary cirrhosis (2011)
  • Author(s): Mitchell MM, Lleo A, Zammataro L, Mayo MJ, Invemizzi P, Bach N, Shimoda S, Gordon S, Podda M, Gershwin ME, Selmi C, LaSalle JM
  • Journal Title: Epigenetics Volume: Jan;6(1) Pages: 95-102
  • Peer Reviewed
• [Journal Article] Significance of periductal Langerhans cells and biliary epithelial cell-derived macrophage inflammatory protein-3α in the pathogenesis of primary biliary cirrhosis. (2011)
  • Author(s): Harada K, Shimoda S, Ikeda H, Chiba M, Hsu M, Sato Y, Kobayashi M, Ren XS, Ohta H, Kasashima S, Kawashima A, Nakanuma Y.
  • Journal Title: Liver Int. Volume: 31(2) Pages: 245-53
  • Peer Reviewed
• [Journal Article] Serum BAFF and APRIL levels in patients with PBC (2010)
  • Author(s): Migita K, Ilyassova B, Kovzel EF, Nersesov A, Abiru S, Maeda Y, Komori A, Ito M, Yano K, Yatsuhashi H, Shimoda S, Ishibashi H, Nakamura M
  • Journal Title: Clin Immunol.Feb Volume: 134(2) Pages: 217-25
  • Peer Reviewed
• [Journal Article] a signpost for biliary inflammation in primary biliary cirrhosis (2010)
  • Author(s): Shimoda S, Harada K, Niiro H, Taketomi A, Maehara Y, Tsuneyama K, Kikuchi K, Nakanuma Y, Mackay IR, Gershwin ME, Akashi K CX3CL1 (fractalkine)
  • Journal Title: Hepatology. Feb Volume: 51(2) Pages: 567-75
  • Peer Reviewed
• [Journal Article] Analysis of HLA-DRB1 polymorphisms in Japanese patients with primary biliary cirrhosis (PBC) The HLA-DRB1polymorphism determines the relative risk of antinuclear antibodies for disease progression in PBC (2010)
  • Author(s): Nakamura M, Yasunami M, Kondo H, Horie H, Aiba Y, Komori A, Migita K, Yatsuhashi H, Ito M, Shimoda S, Ishibashi H; PBC Study Group in NHOSLJ
  • Journal Title: Hepatol Res. May Volume: 40(5) Pages: 494-504
  • NAID: 10026392072
  • Peer Reviewed
• [Journal Article] Kyushu University Liver Disease Study Group.Pegylated interferon a-2b plus ribavirin for older patients with chronic hepatitis (2010)
  • Author(s): Kainuma M, Furusyo N, Kajiwara E, Takahashi K, Nomura H, Tanabe Y, Satoh T, Maruyama T, Nakamuta M, Kotoh K, Azuma K, Shimono J, Shimoda S, Hayashi J
  • Journal Title: C. World J Gastroenterol Volume: 16(35) Pages: 4400-9
  • Peer Reviewed
• [Journal Article] CX3CL1(fractalkine) : a signpost for biliary inflammation in primary biliary cirrhosis. (2010)
  • Author(s): Shimoda S, Harada K, Niiro H, Taketomi A, Maehara Y, Tsuneyama K, Kikuchi K, Nakanuma Y, Mackay IR, Gershwin ME, Akashi K.
  • Journal Title: Hepatology Volume: Feb ; 51(2) Pages: 567-75
  • Peer Reviewed
• [Journal Article] Serum BAFF and APRIL levels in patients with PBC. (2010)
  • Author(s): Migita K, Ilyassova B, Kovzel EF, Nersesov A, Abiru S, Maeda Y, Komori A, Ito M, Yano K, Yatsuhashi H, Shimoda S, Ishibashi H, Nakamura M
  • Journal Title: Clin Immunol Volume: Feb ; 134(2) Pages: 217-25
  • Peer Reviewed
• [Journal Article] Analysis of HLA-DRB1 polymorphisms in Japanese patients with primary biliary cirrhosis (PBC) : The HLA-DRB1 polymorphism determines the relative risk of antinuclear antibodies for disease progression in PBC. (2010)
  • Author(s): Nakamura M, Yasunami M, Kondo H, Horie H, Aiba Y, Komori A, Migita K, Yatsuhashi H, Ito M, Shimoda S, Ishibashi H ; PBC Study Group in NHOSLJ
  • Journal Title: Hepatol Res Volume: May ; 40(5) Pages: 494-504
  • NAID: 10026392072
  • Peer Reviewed
• [Presentation] 原発性胆汁性肝硬変における病因病態の解析 (2012)
  • Organizer: 日本肝臓学会大会
  • Year and Date: 2012-10-20
• [Presentation] 原発性胆汁性肝硬変における胆管上皮の疾患特異的自己抗原発現条件の探索 (2012)
  • Organizer: 日本肝臓学会総会
  • Year and Date: 2012-06-07
• [Presentation] 原発性胆汁性肝硬変モデルマウスにおけるNK/NKT細胞の役割 (2012)
  • Organizer: 日本消化器病学会
  • Year and Date: 2012-04-19
• [Presentation] 原発性胆汁性肝硬変における胆管上皮の疾患特異的自己抗原発現の探索 (2012)
  • Author(s): 下田慎治
  • Organizer: 日本肝臓学会
  • Place of Presentation: 金沢
• [Presentation] 原発性胆汁性肝硬変モデルマウスにおけるNK/NKT細胞の役割 (2012)
  • Author(s): 下田慎治
  • Organizer: 日本消化器病学会総会
  • Place of Presentation: 東京
• [Presentation] 原発性胆汁性肝硬変における病因病態の解析 (2011)
  • Author(s): 下田慎治
  • Organizer: 日本肝臓学会大会
  • Place of Presentation: 福岡
  • Year and Date: 2011-10-20
• [Presentation] 原発性胆汁性肝硬変における胆管破壊に関する新規知見 (2011)
  • Organizer: 日本肝臓学会総会
  • Year and Date: 2011-06-02
• [Presentation] 原発性胆汁性肝硬変における胆管破壊に関する新規知見 (2011)
  • Author(s): 下田慎治
  • Organizer: 日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-06-02
• [Presentation] 原発性胆汁性肝硬変の病態解明と新規治療の可能性 (2011)
  • Organizer: 日本消化器病学会
  • Year and Date: 2011-05-13
• [Presentation] 原発性胆汁性肝硬変の病態解明と新規治療の可能性 (2011)
  • Author(s): 下田慎治
  • Organizer: 日本消化器病学会
  • Place of Presentation: 東京
  • Year and Date: 2011-05-13
• [Presentation] 原発性胆汁性肝硬変(PBC)における免疫異常の基礎とそれに基づく予後予測について (2010)
  • Organizer: 日本肝臓学会大会
  • Year and Date: 2010-10-13
• [Presentation] 原発性胆汁性肝硬変(PBC)における免疫異常の基礎とそれに基づく予後予測について (2010)
  • Author(s): 下田慎治
  • Organizer: JDDW 2010
  • Place of Presentation: 横浜
  • Year and Date: 2010-10-13
• [Presentation] 原発性胆汁性肝硬変における胆管CX3CL1発現に必要なTNFaは、主にTLR4リガンドで単球から産生される (2010)
  • Organizer: 日本肝臓学会総会
  • Year and Date: 2010-05-27
• [Presentation] 原発性胆汁性肝硬変における胆管CX3CL1発現に必要なTNFαは、主にTLR4リガンドで単球から産生される (2010)
  • Author(s): 下田慎治
  • Organizer: 第46回日本肝臓学会総会
  • Place of Presentation: 山形
  • Year and Date: 2010-05-27
• [Presentation] 原発性胆汁性肝硬変における CX3CL1 産生の機序 (2010)
  • Organizer: 日本消化器病学会総会
  • Year and Date: 2010-04-23
• [Presentation] 原発性胆汁性肝硬変におけるCX3CL1産生の機序 (2010)
  • Author(s): 下田慎治
  • Organizer: 第96回日本消化器病学会総会
  • Place of Presentation: 新潟
  • Year and Date: 2010-04-23
• [Remarks]
  • URL: http://www.1nai.med.kyushu-u.ac.jp/